SLE is an aggressive disease which represents an unmet medical need. The disease course is characterized by recurrent flares which currently cannot be predicted and which worsen the status of the patient. Current treatment is symptomatic and based on non-specific immune suppression by glucocorticoids and chemotherapy calling for the identification of new targets for therapeutic intervention. Our previous studies provided strong evidence that interferon-alpha, a potent anti-viral cytokine, contributes to the SLE immune system abnormalities. In SLE patients, this protein is produced in excess and leads to chronic activation of dendritic cells that control other immune cells including B cells and T cells. We have found that interferon alpha-induced dendritic cells are remarkably efficient at activating killer CD8+ T cells. We have now found that SLE patients display increased numbers of activated CD8+CD28+HLA-DR+ effector and CD8+CD28-HLA-DR+suppressor! cells. Our hypothesis is that SLE patients with active disease display considerable alterations in their CD8+ T cell compartments, including effector CD28+ CTLs and suppressor CD28- subsets. We surmise that an excess of killer cells in lupus results in the characteristic tissue damage and explains an excess of dying cells that are considered as key factors in this disease. Simultaneously, the suppressor T cells that normally protect us from the excess of killer cells may be less efficient in SLE than in healthy individuals. To test the validity of our hypothesis, we will first perform an extensive phenotypic characterization of purified activated effector and suppressor CD8+T cells from both healthy individuals and new onset patients followed longitudinally. Second, will characterize the autoreactive repertoire of effector and suppressor CD8+ T cells using the novel EPIMAX technology that we have developed. Third, we will analyze the biological functions of both CD8+T cell subsets from SLE patients, flaring and in remission in comparison to healthy age-matched controls. These studies will help us conclude whether killer CD8+T cells and/or suppressor CD8+ T cells i) can be used as markers and/or predictors of disease activity, ii) represent a valuable new option in lupus therapy.